Heterocyclic amides

Abstract

The present invention relates to certain novel amide derivatives which are pyrido[3,4-d]pyrimidin-7-ylacetamides which are inhibitors of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated. The invention also includes intermediates useful in the synthesis of these amide derivatives, processes for preparing the amide derivatives, pharmaceutical compositions containing such amide derivatives and methods for their use.

What is claimed is: 
     
       1. A compound of formula I: wherein:   R 0  is (1-5C) alkyl;   R 1  is hydrogen, NReRf; or   R 1  is (1-6C)alkyl, (3-6C)cycloalkyl, phenacyl, aryl, acetonyl or heteroaryl (or, where applicable, an N-oxide thereof,) any of which may bear one or more substituents selected from a group consisting of hydroxy, (1-6C)alkyl, (1-4C) alkoxy, (1-4C) acyloxy, COORa, CONRbRc, COO(CH 2 ) 2  NReRf, cyano, SO 2  R 5 , CONRdSO 2  R 5 , NReRf, NRgCOR 6 , NRgCOOR6, NRhCONRiRj, NRkSO 2  R 3 , SO 2  NRlRm, SO 2  NRnCOR 4 , P(O) (ORa) 2 , aryl and heteroaryl (or, where applicable, an N-oxide thereof,); and wherein an aryl or heteroaryl moiety of R 1  or a substituent thereof may bear one or more halogeno, nitro, (1-4C)alkyl, (1-4C) alkoxy or trifluoromethyl groups; wherein   Ra--Rn are independently hydrogen, benzyl or (1-4C) alkyl; or, independently, a group NRbRc, NReRf, NRiRj or NRlRm is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a (1-4C)alkyl or a halogeno substituent at the 4-position; or, independently, a group NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido; and   R 3  -R 6  are independently trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl (or, where applicable, an N-oxide thereof,) in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of (1-4C)alkyl, hydroxy, (1-4C)alkoxy, halogeno or trifluoromethyl;   R 2  is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or a radical of formula BY- in which B is aryl or heteroaryl (or, where applicable, an N-oxide thereof,) and may bear an aryl, or heteroaryl substituent and in which B or an aryl or heteroaryl substituent on B may independently bear one or more substituents selected from the group consisting of halogeno, nitro, (1-6C)alkyl, (3-6C)cycloalkyl, trifluoromethyl, cyano, hydroxy, (1-4C)alkoxy, acetoxy, SO 2  Ro, COORq, CONRrRs; wherein   Rq--Rs are independently hydrogen or (1-4C)alkyl;   Ro is (1-4C)alkyl; and   Y is a direct bond, methylene, ethylene, or trans-vinylene; and   provided that no aliphatic carbon is bonded to more than one nitrogen or oxygen, except as part of a cyclic ketal, or as part of an ester qroup, or where the nitrogen bears a carbonyl group; or   for a compound of formula I which is acidic or basic, a pharmaceutically acceptable salt thereof.   
     
     
       2. A compound as claimed in claim 1 wherein R 1  is hydrogen; or R 1  is (1-6C)alkyl, (3-6C)cycloalkyl, phenacyl, aryl or heteroaryl (or, where applicable, an N-oxide thereof,) any of which may bear one or more substituents selected from a group consisting of hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)acyloxy, COORa, CONRbRc, COO(CH 2 ) 2  NReRf, cyano, SO 2  R 5 , CONRdSO 2  R 5 , NReRf, NRgCOR 6 , NRgCOOR 6 , NRhCONRiRj, NRkSO 2  R 3 , SO 2  NRlRm, SO 2  NRnCOR 4 , P(O)(ORa) 2 , aryl and heteroaryl (or, where applicable, an N-oxide thereof,) and wherein an aryl or heteroaryl moiety of R 1  or a substituent thereof may bear one or more halogeno, nitro, (1-4C)alkyl, ) 1-4  C)alkoxy or trifluoromethyl groups; and Ra-Rn are defined as in claim 1.   
     
     
       3. A compound as claimed in claim 1 or 2 wherein Ro is ethyl or isopropyl; (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; (1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 3-methylbutyl, nl-ethylpropyl, hexyl or 4-methylpentyl; (3-6C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl; aryl is phenyl, indenyl, napthyl; aryl substituted with halOqenO is 4-halophenyl; heteroaryl is furyl, imidazolyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl or quinolinyl (or its N-oxide); lower acyloxy is acetoxy; (1-4C)alkoxy is methoxy, ethoxy, propoxy, isopropoxy or t-butoxy; halogeno is bromo, chloro or fluoro; Ra, Rd Rg, Rh, Rk and Rn independently is hydrogen, methyl, ethyl, isopropyl; NRbRc, NReRf, NRiRj or NRlRm is independently morpholino, 1-pyrloidinyl, piperidino or 1-piperazinyl; R 3  -R 6  independently is methyl, ethyl, isopropyl or phenyl; R 1  is 1-napthylmethyl, 2-(1-napthyl)ethyl, phenethyl, α,α-dimethylphenethyl, methyl, benzyloxycarbonylmethyl or 4-methoxybenzyl; and R 2  is hydrogen or phenyl. 
     
     
       4. A compound as claimed in claim 3 wherein R 0  is isopropyl; and R 1  is 1-naphthylmethyl, 2-(1-naphthyl)ethyl, α,α-dimethylphenethyl, or benzyloxycarbonylmethyl. 
     
     
       5. A compound as claimed in claim 1 wherein R 1  is 1-naphthylmethyl, 2-(1-naphthyl)ethyl, α,α-dimethylphenethyl or benzyloxycarbonylmethyl; and R 2  is hydrogen. 
     
     
       6. A compound as claimed in claim 1 wherein R 1  is 1-naphthylmethyl, 2-(1-naphthyl)ethyl, α,α-dimethylphenethyl or benzyloxycarbonylmethyl; and R 2  is phenyl in which the phenyl may bear one or two halogeno, trifluoromethyl, methyl, hydroxy, methoxy, tert-butoxy, methoxycarbonyl or carboxy substituents. 
     
     
       7. A compound as claimed in claim 6 wherein R 2  is phenyl. 
     
     
       8. A salt as claimed in claim 1 selected from (a) for an acidic compound of formula I, an alkalai metal salt, an alkaline earth metal salt, an aluminum salt, an ammonium salt, or a salt made from an organic base; and   (b) for a basic compound of formula I, an acid-addition salt made with an acid which provides a pharmaceutically acceptable anion.   
     
     
       9. A compound of formula II: ##STR2## wherein R 0  is (1-5C)alkyl; R 1  is hydrogen, NReRf; or   R 1  is (1-6C)alkyl, (3-6C)cycloalkyl, phenacyl, aryl, acetonyl or heteroaryl (or, where applicable, an N-oxide thereof,) any of which may bear one or more substituents selected from a group consisting of hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)acyloxy, COORa, CONRbRc, COO(CH 2 ) 2  NReRf, cyano, SO 2  R 5 , CONRdSO 2  R 5 , NReRf, NRgCOR 6 , NRgCOOR 6 , NRhCONRiRj, NRkSO 2  R 3 , SO 2  NRlRm, SO 2  NRnCOR 4 , P(O)(ORa) 2 , aryl and heteroaryl (or, where applicable, an N-oxide thereof,); and wherein an aryl or heteroaryl moiety of R 1  or a substituent thereof may bear one or more halogeno, nitro, (1-4C)alkyl, (1-4C)alkoxy or trifluoromethyl groups; wherein   Ra--Rn are independently hydrogen, benzyl or (1-4C) alkyl; or, independently, a group NRbRc, NReRf, NRiRj or NRlRm is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a (1-4C)alkyl or a halogeno substituent at the 4-position; or, independently, a group NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido; and   R 3  -R 6  are independently trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl (or, where applicable, an N-oxide thereof,) in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of (1-4C)alkyl, hydroxy, (1-4C)alkoxy, halogeno or trifluoromethyl;   R 2  is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or a radical of formula B.Y- in which B is aryl or heteroaryl (or, where applicable, an N-oxide thereof,) and may bear an aryl, or heteroaryl substituent and in which B or an aryl or heteroaryl substituent on B may independently bear one or more substituents selected from the group consisting of halogeno, nitro, (1-6C)alkyl, (3-6C)cycloalkyl, trifluoromethyl, cyano, hydroxy, (1-4C)alkoxy, acetoxy, SO 2  Ro, COORq, CONRrRs; wherein   Rq--Rs are independently hydrogen or (1-4C)alkyl;   Ro is (1-4C)alkyl; and   Y is a direct bond, methylene, ethylene, or trans-vinylene; and   provided that no aliphatic carbon is bonded to more than one nitrogen or oxygen, except as part of a cyclic ketal, or as part of an ester qroup, or where the nitrogen bears a carbonyl group; or   for a compound of formula II which is acidic or basic, a pharmaceutically acceptable salt thereof.   
     
     
       10. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
       11. A method of treating emphysema comprising administering to a patient in need of treatment thereof a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.